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A Biological-Systems-Based Analyses Using Proteomic and Metabolic Network Inference Reveals Mechanistic Insights into
Natalie N Atabaki1,2,3, Daniel E Coral2, Hugo Pomares-Millan2,4
1Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Medrxiv : the Preprint Server for Health Sciences
|June 12, 2025
Summary
High basal insulin secretion is a key driver of metabolic dysfunction-associated steatotic liver disease (MASLD), especially before type 2 diabetes develops. This study reveals a complex, sex-specific proteo-metabolic network influencing liver fat accumulation.
Area of Science:
- Metabolic Medicine
- Genomics and Proteomics
- Causal Inference
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern.
- Understanding the specific drivers of MASLD, both organ-specific and systemic, is crucial for effective intervention.
- The interplay between metabolic factors, adipose tissue, and liver fat accumulation requires detailed investigation.
Purpose of the Study:
- To identify the causal pathways linking adipose distribution, glycemia, and insulin dynamics to fatty liver.
- To explore the proteomic underpinnings of MASLD in individuals with and without type 2 diabetes (T2D).
- To investigate sex-specific differences in the drivers of hepatic steatosis.
Main Methods:
- Bayesian network analyses were used to model causal relationships between metabolic parameters and liver fat.
- Data from the IMI-DIRECT prospective cohort study included metabolic challenge tests, MRI, serological biomarkers, and Olink proteomics.
- Two-sample Mendelian randomization (MR) was employed to resolve causal directions where Bayesian networks were inconclusive.
Main Results:
- High basal insulin secretion rate (BasalISR) was identified as the primary causal driver of liver fat accumulation in both diabetic and non-diabetic individuals.
- Excess visceral adipose tissue (VAT) showed a bidirectional relationship with liver fat, suggesting a self-reinforcing loop.
- Distinct proteomic drivers were observed between sexes, with GUSB and LEP being most predictive in females and males, respectively.
Conclusions:
- Basal insulin hypersecretion is a modifiable, causal factor in MASLD development, particularly before overt hyperglycemia.
- The study elucidates a multifactorial, sex- and disease-stage-specific proteo-metabolic architecture of hepatic steatosis.
- Proteins like GUSB, ALDH1A1, LPL, and IGFBPs are potential targets for MASLD prevention and treatment.
